Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
  • C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• This invention relates to a class of novel ⁇ -lactam derivatives, which have antibacterial activity and are of value in the treatment of infections in animals, especially mammals including man, caused by a wide range of organisms, particularly Gram-negative organisms.
• the invention also relates to a process for the preparation of such compounds, intermediates for use in the preparation of the compounds and to pharmaceutical compositions comprising the antibacterially active compounds.
• European Patent Application Number 82303821.1 discloses a class of p-lactam antibiotics having an a-formamido (formamidyl) substituent on the carbon atom adjacent to the carbonyl group of the ⁇ -lactam ring. It has now been found that, within this class of compounds, there exist cephalosporin derivatives with outstanding antibacterial properties.
• the present invention provides 7a-formamido cephalosporins of formula (I) or a salt thereof: in which
• the compounds of the invention of formula (I) are quaternary salts and the positive charge on the pyridinium moiety R 4 must always be balanced by a counter anion.
• the counter anion may be present on a negatively charged group within the molecule, such as the carboxylate anion C0 2R 5 , or the counter anion may be present as an external, inorganic or organic anion.
• the formamido group can exist in conformations wherein the hydrogen atoms of the -NH-CHO moiety are cis- or trans-; of these the cis conformation normally predominates.
• aryl includes phenyl and naphthyl optionally substituted with up to five fluorine, chlorine, C 1-6 alkyl, C 1-6 alkoxy, halo (C 1-6 )alkyl, hydroxy, amino, carboxy, C l - 6 alkoxycarbonyl, aryloxycarbonyl, C l - 6 alkoxycarbonyl(C 1-6 )alkyl, nitro, aryloxycarbonyloxy, aryl Cl-6 alkyloxycarbonyloxy, C l - 6 alkyloxycarbonyloxy, C 1-6 alkylcarbonyloxy, arylcarbonyloxy, aryl C 1-6 alkylcarbonyloxy, or aryl C l - 6 alkyloxycarbonyl groups.
• heterocyclyl herein denotes single or fused aromatic or non-aromatic heterocyclic rings,said rings containing up to four hetero atoms selected from oxygen, nitrogen and sulphur and being optionally substituted with u p to three halogen, Cl-6 alkyl, Cl-6 alkoxy, halo(C 1-6 )alkyl, hydroxy, amino, carboxy, C l-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl(C l _ 6 )alkyl, aryl, or oxo groups.
• the heterocyclic ring comprises from 4 to 7 ring atoms, preferably 5 or 6 atoms.
• certain compounds within formula (I) may occur in two or more tautomeric forms; these are included within the scope of the present invention.
• halogen refers to fluorine, chlorine, bromine and iodine.
• the carbon atom marked * in formulae herein is asymmetric and thus compounds of formula (I) may exist as two optically active diastereoisomers.
• the isomer prepared from the D -side chain exhibits the highest antibacterial activity and accordingly the D compound or the DL mixtures are preferred, with the D compound being particularly preferred.
• the compounds of formula (I) with the preferred D-side- chain can be separated from a mixture of both diastereoisomers by conventional methods, or prepared from intermediates that bear a D- side chain.
• the substituted phenyl group for Rl is a phenyl group substituted with up to three groups selected from C l - 6 alkyl, phenyl, halogen, amino, nitro, hydroxy, C 1-6 alkylamido, carbamoyl, carboxy, Cl-6 alkoxycarbonyl, aryloxycarbonyl, halo (C l - 6 ) alkyl, hydroxy(C 1-6 )alkyl, oxo(C 1-6 )alkyl, C l - 6 alkylcarbonyl, arylcarbonyl, C l-6 alkylamino, di(C 1-6 ) alkylamino, or sulphonamido, the amino and hydroxy groups being optionally protected.
• the optional protecting groups for any hydroxy or amino groups attached to a phenyl ring in R 1 are suitably readily cleaved and include in vivo hydrolysable groups as well as groups which may be cleaved by conventional chemical or enzymatic methods.
• protecting groups include those which, when protecting a 3- and/or 4-hydroxy group in R l afford esters or carbonates (both of which may be in vivo hydrolysable), ethers (including silyl ethers) and ketals (for example tetrahydropyranyloxy derivatives, sometimes described as 'THP ethers').
• suitable protecting groups include, for example, those that afford amides and carbamates.
• R l is 3,4-dihydroxyphenyl
• one or both of the hydroxy groups may be protected.
• both hydroxy groups it will be understood that a different protecting group may be used for each hydroxy group, although, more conveniently, the protecting groups used will be the same.
• Suitable hydroxy protecting groups for example for a 3- and/or 4-hydroxy group in R l include formyl and optionally substituted C l-6 alkylcarbonyl and arylcarbonyl groups such as acetyl, chloroacetyl, dichloroacetyl and benzoyl; optionally substituted C 1-6 alkoxycarbonyl and aryl C 1-6 alkoxycarbonyl, for example ethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; and optionally substituted C 2-6 alkenyloxycarbonyl such as allyloxycarbonyl.
• C l-6 alkylcarbonyl and arylcarbonyl groups such as acetyl, chloroacetyl, dichloroacetyl and benzoyl
• C 1-6 alkoxycarbonyl and aryl C 1-6 alkoxycarbonyl for example ethoxycarbonyl, trimethyls
• Suitable hydroxy protecting groups for example for a 3- and/or 4-hydroxy group in R l include aryl, aryl C 1-6 alkyl, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-7 cycloalkyl,and silyl groups.
• optional substituents in protecting groups mentioned hereinabove as being optionally substituted include up to three groups (which may be the same or different) chosen from halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, cyano, nitro, carboxy, carboxylic acid C 1-6 alkyl ester, carbamoyl, amino, mono (C 1-6 ) alkylamino, and di (C 1-6 ) alkylamino.
• alkyl protecting groups for a 3- and/or 4 -hydroxy group in R l include, for example, methyl or ethyl, optionally substituted with (C 1-6 ) alkoxy or (C l - 6 ) alkylthio, for example with methoxy, ethoxy, or methylthio. Further useful protecting groups are methoxyethoxymethyl and (trimethylsilyl)ethoxymethyl.
• R l is 3,4-dihydroxyphenyl
• the hydroxy groups may be protected by an alkylene bridge so that R l becomes, for example, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, or 3,4-[l,l-dimethyl- (methylenedioxy)]phenyl.
• preferred aryl C l-6 alkyl protecting groups for a 3 - and/or 4-hydroxy group in Rl include benzyl and 4-nitrobenzyl.
• silyl protecting groups may be substituted with C l - 6 alkyl and/or phenyl groups and include, for example, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl, isopropyldimethylsilyl, triphenylmethyldimethylsilyl and the like.
• the resulting silyl ethers may be cleaved by methods known in the art, such as those described by T. W. Greene (loc. cit.) or by M. Lalonde and T.H. Chan in Synthesis, 1985 (September), pages 817-845 and references therein.
• a particularly preferred hydroxy protecting group is acetyl.
• the group R l is phenyl, 3-hydroxyphenyl, 3-(C l - 6 alkylcarbonyloxy)phenyl, 3-(aryl C 1-6 alkyloxycarbonyloxy)phenyl, 4-hydroxyphenyl, 4-(C 1-6 alkylcarbonyloxy)phenyl, 4-(aryl C l - 6 alkyloxycarbonyloxy)phenyl, 3 , 4 -dihydroxyphenyl, 3,4-di(C 1-6 alkylcarbonyloxy)-phenyl, 3,4-di(aryl C 1-6 alkyloxycarbonyloxy)phenyl, 2-halo-4,5-di(C 1-6 alkylcarbonyloxy)phenyl, 2-halo-4, 5 -dihydroxyphenyl, 2-halo-4,5-di(aryl C 1-6 alkyloxycarbonyloxy)phenyl, 3,4-methylened
• R l are phenyl, 3,4-dihydroxyphenyl, 3, 4 -diacetoxyphenyl, 2-chloro-4,5-diacetoxyphenyl, 2-chloro-4,5-dihydroxyphenyl, 3,4-methylenedioxyphenyl, 2-thienyl; and 2-furyl.
• Suitable substituents for the 5- or 6- membered heterocyclic group of R 3 or R 2 and R 3 together include C l - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3-7 cycloalkyl or C 4-8 cycloalkenyl groups; aryl; oxo; the hydroxy group optionally substituted by C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, phenyl, pyridyl, pyrimidyl, or benzyl; mercapto; C 1-6 alkylthio; C 1-6 alkylsulphonyl; or the amino group optionally substituted by up to two C 1-6 alkyl, C 2 - 6 alkenyl, C 3 - 7 cycloalkyl, aryl, or benzyl groups.
• two substituents on the ring may form the residue of a 5-or 6-membered carbocyclic ring or the residue of a 5-or 6-membered heterocyclic ring containing up to three hetero atoms selected from oxygen, nitrogen and sulphur.
• Suitable substituents for R 6 include hydrogen, C 1-6 alkyl, C 1-6 alkoxy, carbamoyl, phenyl, pyridyl, (2-N-t-butoxycarbonylamino-2-carboxy)ethyl, C 3-7 cycloalkyl, C 1-6 alkylthio or C 1-6 alkylsulphonate
• R 6 is hydrogen, methyl, ethyl, t-butyl, methoxy, carbamoyl, phenyl, 2-pyridyl, (2-N-t-butoxycarbonylamino-2-carboxy)ethyl, cyclopropyl, n-propyl, iso-propyl, or -CH 2 CH 2 SO 3 - .
• Suitable substituents for R 7 include hydrogen, C l - 6 alkyl, C3-7 cycloalkyl, hydroxy C l - 6 alkyl, C l - 6 alkylcarbonyl, C l-6 alkoxy, halo, or carbamoyl.
• R 7 is hydrogen, methyl, ethyl, hydroxymethyl, hydroxypropyl, acetyl, chloro, methoxy, or carbamoyl.
• Suitable substituents for R 8 include hydrogen, C l-6 alkyl, and C3-7 cycloalkyl.
• R 8 is hydrogen or ethyl.
• X is a group of formula -(CH 2 ) n - wherein n is 3 or 4, preferably 3.
• R 4 is 4-ethylpyridinium, 4-cyclopropylpyridinium, or the 2,3-cyclopentenopyridinium group of formula:
• carboxy protecting groups for R5 are, for example, ester groups including pharmaceutically acceptable in vivo hydrolysable ester groups. It will be appreciated that also included within the scope of the invention are salts and carboxy-protected derivatives, including in vivo hydrolysable esters, of any carboxy groups that may be present as optional substitutents in compounds of formula (I). Also included within the scope of the invention are acid addition salts of any amino or substituted amino groups that may be present as optional substituents in compounds of formula (I).
• ⁇ -lactam antibiotic compounds of the present invention are intended for use in pharmaceutical compositions, .it will be readily appreciated that preferred compounds within formula (I) are pharmaceutically acceptable, i.e. are compounds of formula (Ia) or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof: wherein R l , R 2 , R 3 , R 4 and * are as defined for formula (I) and the group C 02 R is carboxy or a carboxylate anion.
• Non-pharmaceutically acceptable salts of the compound of formula (I) are primarily of use as intermediates in the preparation of a compound of formula (Ia) or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof. Salts within compounds of formula (I) may be prepared by salt exchange in conventional manner.
• non-pharmaceutically acceptable carboxy-protected derivatives of formula (I) for example certain compounds of formula (I) wherein R5 is a readily removable carboxy protecting group, may be used as intermediates in the preparation of pharmaceutically acceptable compounds of formula (Ia) or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof.
• the compounds of formula (I) are betaines, i.e. may also be represented by the formula (Ib).
• a betaine is defined as an uncharged species having isolated non-adjacent cationic and anionic sites, and not possessing a hydrogen atom bonded to the cationic site.
• the counter anion Y is suitably derived from an inorganic acid, preferably a mineral acid.
• the anion Y may suitably be chloride, bromide, iodide, phosphate (i.e. 1/3 PO 4 3- ) or sulphate (i.e. 1/2 S042-).
• Y is chloride
• salts of the sub-formula (Ic) may be prepared from betaines of sub-formula (Ib) by treatment with a dilute mineral acid such as hydrochloric acid.
• Quaternary salts within formula (Ic) may also be prepared by salt exchange in a conventional manner, for example by means of an ion-exchange resin.
• the p-lactam antibiotic compounds of the present invention are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical it will readily be understood that the substantially pure form is preferred as for the ⁇ -Iactam antibiotic compounds. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
• solvent of crystallisation may be present in the crystalline product.
• This invention includes within its scope such solvates.
• some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
• This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
• Suitable readily removable carboxyl protecting groups for the group -C0 2 R 5 include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters.
• the derivative is preferably one which may readily be cleaved.
• Suitable ester-forming carboxyl-protecting groups are those which may be removed under conventional conditions.
• a carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R5 group, for example, acid- and base- catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenolysis under conditions wherein the remainder of the molecule is substantially unaffected.
• Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
• Suitable ester groups of this type include those of part formula (i), (ii), (iii) and (iv) : wherein R a is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, methyl, or phenyl, R b is C 1-6 alkyl, C 1-6 alkoxy, phenyl, benzyl, C 3-7 cycloalkyl, C 1-6 alkyl C 3-7 cycloalkyl, 1-amino C 1-6 alkyl, or 1-(C l - 6 alkyl)amiho C 1-6 alkyl; or R a and R b together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R C represents C 1-6 alkylene optionally substituted with a methyl or ethyl group and R d and R
• suitable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop-l-yl, and (1-aminoethyl)carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and a-ethoxycarbonyloxyethyl; dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; lactone groups such as phthalidyl and dimethoxyphthalidyl; and esters linked to a second ⁇ -lactam antibiotic or to a B-lactamase inhibitor
• a further suitable pharmaceutically acceptable in vivo hydrolysable ester group is that of the formula: wherein R 9 is hydrogen, C 1-6 alkyl or phenyl.
• One particularly preferred sub-group within the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: wherein R l , * and R 4 are as defined with respect to formula ( I ) and R 10 represents hydrogen, C 1-8 alkyl, aryl, or aryl C 1-6 alkyl; R 11 and R 12 are the same or different and represent hydrogen, C l - 6 alkyl, halogen, amino, hydroxy, or C 1-6 alkoxy; or R 11 and R 1 2 form the residue of 5- or 6- membered carbocyclic ring or the residue of a 5- or 6-membered heterocyclic ring containing up to three hetero atoms selected from oxygen, nitrogen and sulphur.
• Suitable C l-6 alkyl groups for the groups R 10, R ll and R 12 in formula ( I I) include methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl.
• R 10 is ethyl or 3-chlorophenyl.
• R ll and R 1 2 are hydrogen.
• R 10 is ethyl and R 11 and R 12 are both hydrogen.
• the antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, according to techniques and procedures per se known in the art with reference to other antibiotics, and the invention therefore includes within its scope a pharmaceutical composition comprising an antibiotic compound according to the present invention such as, for example a pharmaceutically acceptable compound of formula (Ia) or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof together with a pharmaceutically acceptable carrier or excipient.
• an antibiotic compound according to the present invention such as, for example a pharmaceutically acceptable compound of formula (Ia) or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof together with a pharmaceutically acceptable carrier or excipient.
• compositions may be formulated for administration by any suitable route, such as oral or parenteral, or by topical application.
• the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine, tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia
• Suppositories will contain conventional suppository base, eg cocoa-butter or other glyceride.
• fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
• the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
• the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
• agents such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
• Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
• the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• the composition may contain from 0.1% to 99.5% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
• each unit will preferably contain from 50-50 0 mg of the active ingredient.
• the dosage as employed for adult human treatment will preferably range from 100 mg to 12 g per day for an average adult patient (70 kg.), for instance 1 500 mg per day, depending on the route and frequency of administration. Such dosages correspond to approximately 1.5 to 170 mg/kg per day. Suitably the dosage is from 1 to 6g. per day.
• the daily dosage is suitably given by administering a compound of the invention several times in a 24-hour period. Typically, 250 mg. is administered 4 times a day although, in practice, the dosage and frequency of administration which will be most suitable for an individual patient will vary with the age, weight and response of the patients, and there will be occasions when the physician will choose a higher or lower dosage and a different frequency of administration. Such dosage regimens are within the scope of this invention.
• the antibiotic compounds according to the present invention may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics and/or p-lactamase inhibitor may be employed.
• compositions also comprise a compound of formula ( II I) or a pharmaceutically acceptable salt or ester thereof: wherein A is hydroxyl; substituted hydroxyl; thiol; a group of formula S0 2 R 13 wherein R 13 is C 1-6 alkyl; substituted thiol; amino; mono- or di-hydrocarbyl substituted amino; mono- or di-acylamino; an optionally substituted triazolyl group; or an optionally substituted tetrazolyl group as described in EP 0 053 893.
• A is hydroxyl; substituted hydroxyl; thiol; a group of formula S0 2 R 13 wherein R 13 is C 1-6 alkyl; substituted thiol; amino; mono- or di-hydrocarbyl substituted amino; mono- or di-acylamino; an optionally substituted triazolyl group; or an optionally substituted tetrazolyl group as described in EP 0 053 893.
• a further advantageous composition comprises a pharmaceutically acceptable antibiotic compound of the formula (Ia) or a salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier or excipient together with a ⁇ -lactamase inhibitor of formula (IV) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: wherein B is hydrogen, halogen or a group of formula: in which R 14 and R 15 are the same or different and each is hydrogen, C l-6 alkoxycarbonyl, or carboxy or a pharmaceutically acceptable salt thereof.
• ⁇ -lactamase inhibitors include 6-alkylidene penems as described in European patent Application No. 81301683.9 (Publication Number 0 041 768), and European Patent Application No. 85100521.5 (Publication Number 0 154 132) corresponding to laid open published Danish Patent Application No. 324/85.
• p-lactamase inhibitors include 6p-bromopenicillanic acid and salts and in vivo hydrolysable esters thereof and 6p-iodopenicillanic acid and salts and in vivo hydrolysable esters thereof.
• compositions of this invention comprising a ⁇ -lactamase inhibitor are formulated in conventional manner.
• the present invention also includes a method of treating bacterial infections in humans and animals which comprises the administration of a therapeutically effective amount of an antibiotic compound of this invention of the formula (Ia) or a salt or in vivo hydrolysable ester thereof.
• antibiotic compounds of the present invention of formula (Ia) or salts or in vivo hydrolysable esters thereof are active against a broad range of Gram positive and Gram negative bacteria, and may be used to treat a wide range of bacterial infections including those in immunocompromised patients.
• the pharmaceutically acceptable compounds of the invention of formula (Ia) or salts or in vivo hydrolysable esters thereof are of value in the treatment of respiratory tract and urinary tract infections in humans and may also be used to treat mastitis in cattle.
• a particular advantage of the antibacterially active compounds of this invention is their stability to a-lactamase enzymes and they are therefore effective against ⁇ -lactamase producing organisms.
• the present invention further provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of formula ( V ) or a salt thereof: wherein R 4 and R 5 are as hereinbefore defined, wherein any reactive groups may be protected, and wherein the amino group is optionally substituted with a group which permits acylation to take place; with an N -acylating derivative of an acid of formula (V I ):
• R l , R 2 , R 3 and * are defined with respect to formula (I) and wherein any reactive groups may be protected; and thereafter, if necessary or desired, carrying out one or more of the following steps:
• the compounds of formula (la) may be prepared by a similar process, which process further comprises, if necessary, the step of converting the product into a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolysable ester.
• Suitable groups which permit acylation to take place and which are optionally present on the amino group of the starting material of the formula (V) include N-silyl, N-stannyl and N-phosphorus groups, for example trialkylsilyl groups such as trimethylsilyl, trialkyltin groups such as tri-n-butyltin, groups of formula -P.R 16 R 17 wherein R 16 is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, R 17 is the same as R 16 or is halogen or R 1 6 and R 1 7 together form a ring; suitable such phosphorus groups being -P(OC 2 H 5 ) 2 , -P( C 2 H 5)2,
• a preferred group for the above purpose is trimethylsilyl which may suitably be introduced in situ, prior to acylation, by causing an appropriate silylating reagent, e.g. trimethylsilyl chloride, to react with the compound of formula (V).
• an appropriate silylating reagent e.g. trimethylsilyl chloride
• the silylation reaction may suitably be carried out in an inert anhydrous solvent, for example dichloromethane, in an inert atmosphere, preferably under argon.
• An organic base for example N,N-dimethylaniline, may be added to facilitate the reaction.
• the reaction is normally carried out at an elevated temperature, suitably 30-60°C; preferably 40-50°C.
• a reactive N-acylating derivative of the acid (VI) is employed in the above process.
• the choice of reactive derivative will of course be influenced by the chemical nature of the substituents of the acid.
• Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide.
• Acylation with an acid halide may be effected in the presence of an acid binding agent for example, tertiary amine (such as pyridine or dimethylaniline), molecular sieves, an inorganic base (such as calcium carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen halide liberated in the acylation reaction.
• the oxirane is preferably a (C l-6 )- 1,2-alkylene oxide - such as ethylene oxide or propylene oxide.
• the acylation reaction using an acid halide may be carried out at a temperature in the range -50°C to +50°C, preferably -20°C to +20°c, in aqueous or non-aqueous media such as water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof.
• the reaction may be carried out in an unstable emulsion of water-immiscible solvent, especially an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate.
• the acid halide may be prepared by reacting the acid (VI) or a salt or a reactive derivative thereof with a halogenating (eg chlorinating or brominating) agent such as phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosgene.
• a halogenating agent such as phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosgene.
• the N-acylating derivative of the acid ( V I) may be a symmetrical or mixed anhydride.
• Suitable mixed anhydrides are alkoxyformic anhydrides, or anhydrides with, for example, carbonic acid monoesters, trimethyl acetic acid, thioacetic acid, diphenylacetic acid, benzoic acid, phosphorus acids (such as phosphoric, phosphorous, and phosphinic acids) or aromatic or aliphatic sulphonic acids (such as p-toluenesulphonic acid or methanesulphonic acid).
• phosphorus acids such as phosphoric, phosphorous, and phosphinic acids
• aromatic or aliphatic sulphonic acids such as p-toluenesulphonic acid or methanesulphonic acid.
• Alternative N-acylating derivatives of acid ( V I) are the acid azide, or activated esters such as esters with 2-mercaptopyridine, cyanomethanol, p-nitrophenol,, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, N-hydroxy succinimide, N -hydroxybenzotriazole, or 8 -hydroxyquinoline; or amides such as N -acylsaccharins, N -acylthiazolidin-2-thione or N-acylphthalimides; or an alkylidene iminoester prepared by reaction of the acid (VI) with an oxime.
• esters such as esters with 2-mercaptopyridine, cyanomethanol, p-nitrophenol,, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, N-hydroxy succinimide, N -hydroxybenzotriazole
• N-acylating derivatives of the acid ( V I) include the reactive intermediates formed by reaction in situ with a condensing agent such as a carbodiimide, for example, N,N'-diethyl-, dipropyl- or diisopropylcarbodiimide, N,N'-di-cyclohexyl- carbodiimide, or N-ethyl-N'-[3-(dimethylamino)propyl]-carbodiimide; a suitable carbonyl compound, for example, N,N'-carbonyldiimidazole or N,N'-carbonyldi- triazole; an isoxazolinium salt, for example, N-ethyl-5-phenylisoxazolinium-3-sulphonate or N-t-butyl-5-methylisoxazolinium perchlorate; or an N-alkoxycarbonyl 2-alkoxy-l,2-dihydroquinoline, such as
• condensing agents include Lewis acids (for example BBr 3 - C 6 H 6 ); or a phosphoric acid condensing agent such as diethylphosphorylcyanide.
• the condensation reaction is preferably carried out in an organic reaction medium, for example, methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran.
• a further method of forming the N-acylating derivative of the acid of formula (VI) is to treat the acid of formula (VI) with a solution or suspension preformed by addition of a carbonyl halide, preferably oxalyl chloride, or a phosphoryl halide such as phosphorus oxychloride, to a halogenated hydrocarbon solvent, preferably dichloromethane, containing a lower acyl tertiary amide, preferably N,N-dimethylformamide.
• the N-acylating derivative of the acid of formula (VI) so derived may then be caused to react with a compound of formula ( V ).
• the acylation reaction may conveniently be carried out at -40 0 to +30 o C, if desired in the presence of an acid binding agent such as pyridine.
• a catalyst such as 4-dimethylaminopyridine may optionally also be added.
• a preferred solvent for the above acylation reaction is dichloromethane.
• a preferred intermediate of formula (V) has the formula (VA): wherein R 4 is as hereinbefore defined.
• a preferred process for the preparation of a compound of formula (I) comprises treating a compound of formula (VA): wherein R 4 is hereinbefore defined, wherein any reactive groups may be protected, and wherein the amino group is optionally substituted with a group which permits acylation to take place; with an N-acylating derivative of an acid of formula (VI): wherein R l , R 2 , R 3 and * are defined with respect to formula (I) and wherein any reactive groups may be protected; and thereafter, if necessary or desired, carrying out one or more of the following steps:
• the compounds of formula (Ia) may be prepared by a similar process, which process further comprises, if necessary, the step of converting the product into a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolysable ester.
• a further preferred intermediate of formula ( V ) as hereinabove described has the formula (VII) or is an acid addition salt thereof: wherein R 4 is defined with respect to formula ( I ); R X is hydrogen or a readily removable carboxy protecting group; and Z is an inorganic or organic anion present in the appropriate stoicheiometric proportion to balance the positive charge R 4.
• Suitable readily removable carboxy protecting groups for R X include those listed hereinabove as suitable readily removable carboxy protecting groups for R 5 .
• the compounds of formula (I) may therefore also suitably be prepared by reacting a compound of formula (VII) as hereinabove defined or an acid addition salt thereof, wherein any reactive groups may be protected,with an N-acylating derivative of an acid of formula (VI) as hereinbefore defined (wherein any reactive groups may be protected); and thereafter, if necessary or desired, carrying out one or more of the following steps:
• a preferred group which may be introduced onto the amino group in the compound of formula (VII) is trimethylsilyl.
• the silylation reaction may be carried out in situ, prior to the acylation reaction, with a silylating agent that does not require concomitant addition of base.
• Suitable silylating agents include, for example, N-(trimethylsilyl)-acetamide, N,O-bis(trimethylsilyl)acetamide, N,O-bis (trimethylsilyl)trifluoroacetamide, N-methyl-N-trimethylsilylacetamide, N-methyl-N-trimethylsilyl- trifluoroacetamide, N,N'-bis(trimethylsilyl)urea, and N,O-bis(trimethylsilyl)carbamate.
• a preferred silylating agent is N-(trimethylsilyl)acetamide.
• the silylation reaction may suitably be carried out in an inert, anhydrous organic solvent such as dichloromethane at room temperature or at an elevated temperature, for example 30 - 60°C, preferably 40 - 50°C.
• the above process may optionally be carried out in the presence of a small quantity, for example 0.1 equivalents, of a silyl halide, for example a tri(C l-6 )alkylsilyl halide, especially trimethylsilyl chloride.
• a silyl halide for example a tri(C l-6 )alkylsilyl halide, especially trimethylsilyl chloride.
• Z in compounds of formula (VII) are chloride and bromide.
• a reactive N -acylating derivative of the acid (VI) is employed in the preparation of a compound of formula (I) from a compound of formula ( V II), the choice of reactive derivative being influenced by the chemical nature of the substituents of the acid of formula (VI).
• Suitable N - acylating derivatives of the acid ( VI ) include those listed hereinbefore as suitable for use in the process for preparing a compound of formula ( I ) from a compound of formula ( V ). Methods for preparing such suitable N -acylating derivatives are as hereinabove described.
• a preferred N-acylating derivative of the acid of formula (VI) is an acid halide, most preferably the acid chloride, which advantageously may be freshly prepared from the corresponding acid (VI) before use.
• Suitable halogenating agents for preparing acid halides from the acid of formula (VI) are hereinbefore described.
• Preferred halogenating agents include oxalyl chloride, thionyl chloride, and phosgene.
• the group C0 2 R x is preferably carboxy.
• R X preferred groups for R X are diphenylmethyl (benzhydryl) and tri (C 1-6 alkyl)silyl, especially trimethylsilyl.
• the trimethylsilyl group may suitably be introduced onto the 4- carboxy group using silylating agents listed hereinabove as suitable for silylating the amino group in compounds of formula (VII).
• the compounds of formula (V) herein which are, inter alia, intermediates for the compounds of formula (I) as hereinbefore defined may be prepared by reacting a compound of formula (VIII) or acid addition salt thereof: wherein R X is as hereinbefore defined, R 19 is a leaving group and y is 0 or 1; with a substituted pyridine of formula (IX), (X) or (XI): wherein R 6 , R 7 , R 8 , and X are as hereinbefore defined; with the proviso that when R 19 is an acyloxy group, the group C0 2 R x must be in the free acid form or a salt thereof; and thereafter if necessary:
• Suitable leaving groups R 19 include halide such as iodide or bromide or an acyloxy group such as, for example the acetoxy group.
• R 1 9 is an acetoxy group or a bromine atom.
• a particularly suitable acid addition salt of the starting material of the formula (VIII) is the trifluoroacetic acid salt.
• R 19 is an acetoxy group
• the conversion of compounds of formula (VIII) into compounds of formula (V) is preferably carried out in an aqueous medium, if necessary with a water-miscible organic solvent such as acetone present to give a homogeneous solution.
• the reaction may suitably be conducted in the presence of an alkali metal iodide, e.g. sodium iodide, or an alkali metal thiocyanate, e.g. potassium thiocyanate, and is generally carried out at an elevated temperature, for example between 40 and 80°C, and preferably at about 60°C.
• the product When the reaction is complete (as adjudged, for example, by an analytical method such as reversed phase HPLC), the product may be isolated by chromatography on a suitable resin, for example 'Diaion HP 20SS' resin (obtained from Mitsubishi Chemical Corporation), and the product may thereafter, if necessary or desired, be modified to give a compound of formula (V) in which any reactive group which is present on R 4 may be protected.
• a suitable resin for example 'Diaion HP 20SS' resin (obtained from Mitsubishi Chemical Corporation)
• Acid addition salts of the compound of formula (VII) as hereinbefore defined may suitably be prepared by reacting a compound of formula (VII) with a mineral acid.
• the acid addition salt of the compound of formula (VII) as hereinbefore defined may suitably be prepared by reacting a compound of formula (VA) with a mineral acid; and also, if necessary or desired, converting the carboxy group into a group C0 2R X .
• the above reactions may suitably be carried out in an aqueous medium at ambient temperature by addition of a dilute mineral acid, generally in the presence of a water-miscible organic solvent such as acetone, ethanol, propan-l-ol or propan-2-ol.
• a dilute mineral acid generally in the presence of a water-miscible organic solvent such as acetone, ethanol, propan-l-ol or propan-2-ol.
• the reaction mixture may be chilled to 0 - 10°C, generally to less than 5 0 C, to facilitate isolation of the product.
• the mineral acid used to convert a compound of the formula (VA) into an acid addition salt of a compound of formula ( V II) has the formula HZ wherein Z is as defined with respect to formula (VII).
• a particularly suitable mineral acid, for converting a compound of formula (VA) into an acid addition salt of a compound of formula (V I I) is dilute hydrochloric acid.
• the compounds of formula (I) may also suitably be prepared by reacting a compound of formula ( X II): wherein R l , R 4 , R 5 and * are as hereinbefore defined; the a-amino group is optionally substituted with a group which permits acylation to take place; and any reactive groups may be protected; with an N-acylating derivative of an acid of formula (XIII): wherein any reactive groups may be protected; and thereafter, if necessary or desired, carrying out one or more of the following steps:
• Suitable amino-protecting groups R 20 are those well known in the art which may be removed under conventional conditions without disruption of the remainder of the molecule.
• amino-protecting groups for R 20 include benzyl optionally substituted in the phenyl ring by one or two substituents selected from C 1-4 alkyl, C l - 4 alkoxy, trifluoromethyl, halogen, or nitro; C 1-4 alkoxycarbonyl optionally substituted by up to three halogen atoms, for example tert-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl; benzyloxycarbonyl optionally substituted as for benzyl above; allyloxycarbonyl; or trityl.
• Compounds of formula (XII) may also be prepared by reacting a compound of formula (V) as hereinbefore defined with an N-acylating derivative of an a-azido acid of formula ( X V): wherein R l and * are as hereinbefore defined; followed by reduction of the azido group to an amino group by conventional methods, for example by catalytic hydrogenation or by reaction with triphenylphosphine followed by hydrolysis of the resultant phosphinimine.
• Compounds of formula ( X II) may also be prepared by reaction a compound of formula (V) as hereinbefore defined with an N-acylating derivative of an acid of formula (XVI): wherein R l and * are as hereinbefore defined; and hereinafter converting the phthalimido groups into an amino group by conventional methods.
• the present invention further provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of the formula (XVII). wherein R l , R 2 , R 3 , R X , R 19 , y, and * are as hereinbefore defined; with a substituted pyridine of formula (IX), ( X ) or (XI) as hereinbefore defined; with the proviso that when R 1 9 is an acyloxy group, the group C0 2 R x must be in the free acid form or a salt thereof; and thereafter if necessary:
• Suitable leaving groups R 19 include halide such as iodide or bromide or an acyloxy group such as, for example, the acetoxy group.
• the present invention also provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of the formula (XVIII): wherein R 1 , R 2 , R 3 , R 4 and * are as hereinbefore defined, and wherein any reactive groups may be protected, R X is hydrogen or a readily removable carboxy protecting group; and R 21 is C 1-6 alkyl, aryl or benzyl; with a heavy metal ion such as mercury, silver, thallium, lead or copper; and thereafter in situ with a nucleophilic derivative of formamide; and thereafter, if necessary, carrying out one or more of the following steps:
• the present invention provides a process for the preparation of a compound of formula (I) which process comprises treating a compound of formula (XIX): wherein R l, R 2, R 3, R 4 , * , R X and R 21 are as defined for formula (XVIII) and wherein any reactive groups may be protected; with a nucleophilic derivative of formamide; and thereafter, if necessary, carrying out one or more of the following steps.
• the present invention further provides a process for the preparation of a compound of formula (I) which process comprises formylating a compound of formula (XX): wherein R l, R 2, R 3, R 4, R X , and * are as hereinbefore defined and wherein any reactive groups may be protected; and thereafter, if necessary, carrying out one or more of the following steps.
• Suitable formylating agents include the reagent 4-formyl-2-methyl-l,3,4-thiadiazolin-5-thione (see H . Y azawa and S. Goto, Tetrahedron Letters, 1985, 26, 3703-3706), or mixed anhydrides such as formic acetic anhydride.
• the reaction may suitably be carried out in a temperature in the range -50°C to 30°C in aprotic solvent such as, for example, dichloromethane, chloroform, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide, or dimethylsulphoxide, in the presence of a tertiary base.
• a preferred tertiary base employed in the reaction is a base of the pyridine type, such as pyridine, lutidine or picoline.
• a further process for preparing compounds within formula (XX) comprises treating a compound of formula (XIX) with ammonia.
• a process for preparing compounds of formula (I) comprises formamidylating a compound of formula (XXI): wherein L is S R 21 , SOR 21 or NH2; and R l , R 2 , R 3, R 4, R x , R 21 and * are as hereinbefore defined.
• the antibiotic compounds of the present invention are active against a wide range of Gram-negative and Gram-positive organisms including E.coli such as, for example ESS, JT4, JT425 and NCTC 10418; Pseudomonas Spp. such as Ps.aeruginosa for example 10662 and Dalgleish; Serratia marcescens US32; Klebsiella aerogenes A; Enterobacter cloacae Nl; P.mirabilis such as, for example C977 and 889; P .morganii; P.rettgeri; B.subtilis; Staph aureus such as, for example Oxford and Russell; N.catarrhalis 1502; Strep faecalis I; ⁇ -Haemolytic Strep CN10.
• E.coli such as, for example ESS, JT4, JT425 and NCTC 10418
• Pseudomonas Spp. such as Ps.aeruginosa for example
• reaction was monitored by reverse phase HPLC.
• reaction was complete, the mixture was diluted with dichloromethane and extracted with water (x3). The combined aqueous extracts were washed with dichloromethane (x2). The aqueous phase was concentrated at reduced pressure and the concentrate chromatographed on HP20SS resin, eluting initially with water, then acetone/water mixtures. The product containing eluant was concentrated at reduced pressure, then lyophilised to give the title compound (395mg, containing ca.
• the pH of the mixture was maintained at 8.5/ 9.0 by the addition of more 2.5% (w/v) aqueous sodium carbonate solution.
• the reaction was monitored by reverse phase HPLC. After ca. 40 min, the crude mixture was chromatographed on HP20SS, eluting initially with water then acetone/water mixtures. The product containing eluant was concentrated at reduced pressure and the concentrate lyophilised to give the title compound (213mg, containing ca.
• Example l(b) in Example l(b) to give the title compound (137mg; 66%); ⁇ max (H 2 0) 226 (e m 21282) and 255nm (13240); v max (KBr) 3410, 3290, 1780, 1710 (sh), 1683, 1635, and 1616cm -1 ; 6 H (D 2 0) (D-isomer; major rotamer) 1.15 (3H, t, J 7.lHz), 1.38 (9H, s), 2.75 and 3.36 (together 2H, ABq, J 17.7Hz), 3.47 (2H, q, J 7.lHz), 3.55-3.75 (2H, m), 3.80-4.10 (2H, m), 5.12 and 5.30 (together 2H, ABq, J 14.4Hz), 5.31 (lH, s), 5.47 (lH, s), 7.20-7.55 (5H, m), 8.04 (2H, d, J 6.2Hz), 8.12 (lH,
• MIC values of compounds of the invention against E coli DC O, K pneumoniae T767, and P aeruginosa NCTC 10662 were determined by serial dilution in a nutrient agar (from Oxoid Ltd., Basingstoke, England). The plates were inoculated with 10 4 colony forming units and incubated overnight at 37°C. The MI C values recorded in Table 1 were the lowest concentration of antibiotic to inhibit growth. Comparative data for 7a-formamido-3-(pyridiniummethyl)-7 ⁇ -(thien-2-yl-acetamido)-ceph-3-em-4-carboxylate (Compound A), disclosed in European Patent Application No. 82303821.1 (Publication Number 0 071 395), are also given.

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• 1986
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